DESCRIPTION: (Applicant's Abstract) Mechanisms that regulate opioid receptors play important roles in opiate drug action and are of fundamental importance to the biology of addiction. The proposed studies focus on the regulation of opioid receptors by rapid endocytosis. This process is of particular interest because (a) it distinguishes between structurally homologous types of cloned opioid receptor (delta, mu, and kappa); and (b) it is differentially regulated by opioid peptides and morphine. I propose to elucidate molecular mechanisms that mediate and regulate opioid receptor endocytosis, with the goal of understanding the remarkable type-selectivity and ligand-specificity of this process. The Specific Aims of the proposed studies are (1) to define endocytotic mechanisms that determine the type-selectivity and ligand-specificity of opioid receptor endocytosis, (2) to identify receptor domains that mediate type-selective differences in the endocytosis of cloned opioid receptors, and (3) to examine the effect of protein phosphorylation sites on type-selective and ligand-specific endocytosis of opioid receptors. These studies are directly relevant to the biology of opiate action and addiction. In addition, because the ability of different full agonist ligands to differentially regulate receptor endocytosis is a novel finding, these studies have general importance to the cell biology of G protein-coupled receptors.